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Integrin Alpha 4 Inhibition Prolongs the Survival of NSG Mice Engrafted with CD19-Negative Post-CART19 Relapsed B-ALL
Hye Na Kim1, Samantha Hurwitz1, Tatiana Fourfouris1
1Division of Hematology, Oncology and Blood and Marrow Transplantation, Department of Pediatrics, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA.
Integrin α4 is a stable target on B-cell acute lymphoblastic leukemia (B-ALL) cells after anti-CD19 chimeric antigen receptor T-cell (CART19) therapy. Targeting integrin α4 with Natalizumab disrupted leukemia cell adhesion and improved survival in preclinical models.
Area of Science:
- Hematology
- Immunology
- Oncology
Background:
- Relapsed and refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) after anti-CD19 chimeric antigen receptor T-cell (CART19) therapy presents a significant clinical challenge.
- Antigen loss, specifically CD19, is a primary mechanism of resistance to CART19 therapy.
Purpose of the Study:
- To identify stable biomarkers on B-ALL cells post-CART19 therapy.
- To evaluate integrin α4 as a potential therapeutic target for overcoming CART19 resistance.
Main Methods:
- CRISPR/Cas9 was used to knock out CD19 in primary B-ALL cells to assess integrin α4 expression.
- The anti-integrin α4 antibody Natalizumab (NZM) was used to disrupt leukemia cell adhesion to VCAM-1 and stromal cells.
- Therapeutic efficacy of NZM was evaluated in NSG mice engrafted with post-CART19-relapsed B-ALL.
Main Results:
- Integrin α4 expression was consistently observed on B-ALL cells before and after CART19 therapy, independent of CD19 expression.
- NZM treatment effectively disrupted leukemia cell adhesion to the microenvironment.
- NZM treatment significantly prolonged survival in preclinical models of post-CART19 relapsed B-ALL.
Conclusions:
- Integrin α4 is a stable and promising biomarker for B-ALL cells following CART19 therapy.
- Targeting integrin α4 with Natalizumab offers a potential strategy to overcome CART19 resistance in B-ALL.
